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Peter G. Schulam, MD, PhD

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Breakthroughs is published annually to highlight research and clinical advances from

Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven.

Yale Cancer Center

333 Cedar Street, PO Box 208028

New Haven, CT 06520-8028

yalecancercenter.org

© Copyright 2015, Yale Cancer Center.

All rights reserved. No part of this periodical may be reproduced by any means,

prints, electronic, or any other, without prior written permission of the publisher.

Editorial Office

Yale Cancer Center

100 Church Street South, Suite 160

New Haven, CT 06519

[email protected]

On the CoverDr. Andrea Silber with Maria Castellani,

Wendy Ormond, and Marta Vega

2 Director’s Letter

features 4 Detecting Hereditary Kidney Cancer

Once assumed a sporadic disease, newer

research suggests that five to eight percent of

kidney cancer is genetic and Dr. Brian Shuch,

director of Smilow Cancer Hospital’s Hereditary

Kidney Cancer Program believes this number

will continue to rise.

7 Bringing Clinical Trials into our Communities

Dr. Andrea Silber’s close relationship with her patients and growing network in the New Haven community is building trust and expanding clinical trial participation through a new initiative called OWN IT.

10 Accelerating Development of New Drugs

The new Yale Cancer Therapeutic Accelerator Program (Yale CTAP) will focus on generating new cancer drugs and accelerating their development in much the same way as biotech startups.

12 Love Knows no Bounds, Not Even Cancer

Josh Scussell was diagnosed with T Cell Lymphoma at 23. His long road to cure included two transplants and several years. Throughout, Heather was by his side and they married one year and three months after his final transplant.

research programs 16 Radiobiology and Radiotherapy

Imaging the Epidermal Growth Factor Receptor

18 Cancer Prevention and ControlTexting to Check in on Patients

20 Cancer ImmunologyThe Immune System and the Risk of Lymphoma

22 Virus and Other Infection-associated Cancers

The Links Between Typhoid, Bacteria, and Cancer

24 Developmental TherapeuticsMolecules That Seek and Destroy Mutant Proteins

26 Cancer Genomics, Genetics, and EpigeneticsBioinformatics Boosts Cancer Research

28 Signal TransductionDecoding the Signals of Metastasis

leadership and membership 30 Yale Cancer Center and

Smilow Cancer Hospital at Yale-New Haven Leadership

32 Yale Cancer Center Membership

1yalecancercenter.org | Yale Cancer Center

10

12

7

Over the last year, Yale Cancer Center and Smilow

Cancer Hospital at Yale-New Haven have focused

greater emphasis on the need to provide education and

community-based outreach initiatives that are important

to our patients. Yale Cancer Center and Smilow Cancer

Hospital recognize the importance of impacting the

community we serve – the communities in which our

patients as well as our physicians, faculty, scientists, and

employees share. New Haven and its surrounding towns

provide us with an opportunity to care for and educate

a diverse population on cancer prevention, screening,

and treatment.

In the months ahead, we will implement a highly

organized effort to expand cancer screening in diverse

populations, particularly in men and women at the

highest risk of developing certain cancers. We will

establish important initiatives aimed at increasing

the opportunity for all patients in our community to

access the most recent advances in treatment through

our clinical trials. With support from many of their

colleagues, Beth Jones, PhD, MPH and Andrea Silber,

MD are partnering to lead these efforts.

Our refocused efforts in clinical trial outreach and

patient navigation continues Dr. Silber’s long tradition of

patient education in the community of New Haven. In

2015, Dr. Silber launched OWN IT (Oncologists Welcome

New Haven Into Trials) to support more minorities as

they consider participation in clinical trials. New Haven’s

population is approximately two-thirds African American

and Latino and we recognize the need for additional

support for this diverse population during cancer

treatment. What makes these efforts so crucial, is the

need to ensure the research that cancer centers do across

the country reflects the diverse population of the United

States. Although the national cancer research community

often falls short of this aspiration, Yale Cancer Center

is committed to doing our part to help achieve this

important goal.

Yale Cancer Center also continues to expand new

scientific programs and recently launched the Yale

Cancer Therapeutic Accelerator Program (Yale CTAP)

to improve our ability to discover compounds that may

be able to be rapidly converted to new treatments for

patients. This new program, led by Craig Crews, PhD

and Mark Lemmon, PhD, will facilitate the advancement

of these compounds or drugs from Yale Cancer Center

laboratories. The program helps to provide Yale Cancer

Center drug discovery teams with the support needed

to increase the likelihood of commercialization of those

compounds. I look forward to sharing some of the

success stories from Yale CTAP over the coming year as

Dr. Crews and Dr. Lemmon begin to build the team and

infrastructure needed to optimize drug discovery at Yale

Cancer Center.

The momentum developed over the first 5 years at

Smilow Cancer Hospital continued to expand in 2015.

In June, we welcomed Saint Francis Hospital in Hartford

to our Smilow Cancer Care Network and have expanded

access to Yale Cancer Center physicians along the eastern

shoreline from Guilford to Old Saybrook, and most

recently to Waterford. Exceptional care and access to

clinical trials is now available at 12 locations around the

state of Connecticut. Yale’s clinical trial accrual also

reached an all-time high in 2015 and we continue to strive

to make the newest treatment options available to our

patients through clinical trial participation.

In addition, Yale Cancer Center’s 7 Research Programs

and nearly 350 members are continuing their pursuit to

understand cancer and find ways to reduce its impact on

patients in our community. New discoveries happen daily

as scientists from our laboratories and physicians from

our Disease Aligned Research Teams (DARTs) at Smilow

Cancer Hospital combine their efforts in unique and

impactful ways. Many highlights from 2015 are featured

in this edition of Breakthroughs and I look forward to

sharing new research advances and outcomes from our

laboratories and clinics with you in the year to come.

Sincerely,

Peter G. Schulam, MD, PhD

Director, Yale Cancer Center and Physician-in-Chief,

Smilow Cancer Hospital at Yale-New Haven (Interim)


Brian Shuch, MD, Assistant

Professor of Urology and of

Radio logy and Biomedica l

Imaging, has a patient in her 70s who

probably wouldn’t be alive if not for the

Hereditary Kidney Cancer Program, which

Dr. Shuch directs. Before Dr. Shuch saw her,

she had lost a kidney to cancer and wasn’t

responding to standard chemotherapy. Her

doctor referred her to Dr. Shuch’s program,

which specializes in kidney cancers caused by

heredity or acquired genetic mutations.

As always, Dr. Shuch delved into her

family history. Her mother had died of kidney

cancer. So had both of her own children, who

hadn’t responded to standard treatment of

the disease. Dr. Shuch suspected an inherited

syndrome. A genetic test confirmed it: she had

a variant of an uncommon kidney cancer called

4

Brian Shuch, MD


hereditary leiomyomatosis and renal cell cancer (HLRCC). He put her on

an experimental regimen of chemotherapy not typically used against kidney

cancer, but known to be effective against HLRCC. A year later, her cancer had

essentially disappeared.

Smilow Cancer Hospital launched the Hereditary Kidney Cancer Program in 2013 precisely to

help such patients and to educate the physicians who diagnose them. Kidney cancer is one of the most common

forms of the disease, with an estimated 61,500 new cases each year. Scientists once assumed that kidney cancers occur

sporadically, but newer research suggests that five to eight percent stem from genetic predisposition. Dr. Shuch believes

this number will continue to rise.

“We haven’t even begun to scratch the surface of inherited predisposition,” he said. “Lineage studies show that about

80 percent of kidney cancers cluster in about a quarter of the population, strong evidence that kidney cancer has a strong

hereditary basis.”

Currently, however, genetic syndromes associated with kidney cancer often go unrecognized by physicians, to the

detriment of patients. The standard of care used against sporadic forms of the disease may be ineffective against hereditary

syndromes. Certain syndromes are associated with asymptomatic signs of kidney cancer. Four syndromes, for example,

can manifest themselves as skin problems. Few physicians have the training to recognize these signs. Similarly, a syndrome

called Von Hippel-Lindau syndrome may be accompanied by retinal tumors.

“I’ve had patients lose their vision by a delay in the diagnosis of manifestations outside the kidney,” said Dr. Shuch.

“A urologist and oncologist who are focused on their areas of expertise often miss subtle signs in the physical exam or

cues in the

family history

t h a t w i l l r a i s e

alarms to an experienced

multidisciplinary team.” The

team at Yale includes urologists, pathologists,

dermatologists, geneticists, and genetic counselors.

Just a day earlier, Dr. Shuch had seen a patient referred

to him by the team’s dermatologist because of a skin

lesion called a leiomyoma, sometimes a sign of HLRCC.

When Dr. Shuch teased out the patient’s family history, he

learned that all three of his sisters had had their uteruses

removed in their 30s because of fibroids, another sign

of HLRCC, and his 23-year-old nephew had advanced

kidney cancer.

“That patient doesn’t have any symptoms of kidney

cancer,” said Dr. Shuch, “but he absolutely needs testing

and genetic screening for a presumed diagnosis of

HLRCC. We’ve had patients whose lives were potentially

detecting hereditary KIDNEY CANCER

saved by identifying an asymptomatic kidney cancer

through screening and treating it before dissemination.”

Part of Dr. Shuch’s mission is to educate physicians to

take a comprehensive family history, and to be alert for

signs that a patient should be referred to his program for

evaluation and genetic testing. One of the clearest signs

is early onset of kidney cancer. The average age for a

diagnosis is 64, and the cancer rarely hits people younger

than 45 – but the inherited forms often strike before that

age. Other signs: unusual pathology, bilateral disease, and

multifocal disease.

Dr. Shuch and his colleagues have developed a genetic

screening panel for the known syndromes, which at this

point number about 15. Yale is one of the first centers

with such a panel, which allows the team to test multiple

genes at once.

Genetic testing is crucial not only for patients with

symptoms of hereditary kidney cancer, but for their

parents, siblings, and children. Early detection can

mean the difference between life and death. HLRCC,

for instance, is one of the most aggressive syndromes.

Before Dr. Shuch’s program began, Yale had not

identified a single patient with HLRCC, but in the past

two years, nine families have been diagnosed with it.

“Rather than lumping them in with generic kidney

cancer and treating them the same,” explained Dr.

Shuch, “we have been able to offer them unique treatment strategies focused on the genetic alterations associated with

that syndrome.”

That has prolonged lives. James Uhl, for instance, was 45 when diagnosed with kidney cancer. The disease had spread

to his liver, lungs, bones, brain, eyes, and lymph system. He was referred to Dr. Shuch, who found HLRCC. In January

2014, Dr. Shuch removed Mr. Uhl’s left kidney, part of his liver, and multiple lymph nodes, then put him on a unique

regimen not designed for kidney cancer but often effective against this particular syndrome. It worked well for six

months, an unusual span against a cancer so advanced. After trying several other regimens, in late 2015 Dr. Shuch got

Mr. Uhl into a clinical trial at the NCI. Dr. Shuch doubts that Mr. Uhl would have had the last two years with his family

without the Smilow program.

“Brian’s knowledge of the disease has offered me tremendous guidance,” said Mr. Uhl, who remains optimistic.

“Without the work being done by him and his team, little would be known about this aggressive disease. Because of

their research, more and more treatment options are going into trial phases, which gives patients like me a lot of hope.”

He’s also grateful that Dr. Shuch identified his syndrome, because his children, 10 and 8, can be tested very early for the

gene. “I’ll be able to potentially save my children’s lives,” he said.

As knowledge about the genetics associated with each kidney cancer syndrome grows, targeted therapies become

possible. “Rather than treating kidney cancer as one disease,” said Dr. Shuch, “we’ve learned it’s a group of cancers

arising from the same organ, but all very different.”

New knowledge is changing treatment in other ways as well. For instance, three of the syndromes produce kidney

cancers that pose no risk of metastasis until the tumor reaches a certain threshold. Until then, the cancer can be

managed, and patients can be spared unnecessary surgery—that is, if the syndromes are identified early, which is why

testing can be so important.

In 2016 the program will expand to other urologic cancers with heritable syndromes such as prostate, bladder, and

testicular cancers. Dr. Shuch and his colleague are also planning a tele-genetic counseling service so that other cancer

centers can benefit from Yale’s expertise.

“So much of this is not just cancer treatment,” explained Dr. Shuch, “it’s preventing the delayed management of new

tumors by aggressive screening. A delay in diagnosis could be the difference between cure and cancer dissemination.”

6 Yale Cancer Center | Year in Review 20158 Yale Cancer Center | Year in Review 2014

Henry Baker

PAVING THE WAY FOR THE FUTURE:Tale of TriumphHENRY BAKER’S Communitiesinto our

Andrea Silber, MD

Andrea Silber, MD, Associate Clinical

Professor of Medicine, has never forgotten one of

her first patients in New Haven nearly thirty years ago, a

young black mother of four. She had breast cancer but had

never been treated. Within a week, she was dead.

“It was incredibly sad, and it stuck with me,” said Dr.

Silber, a medical oncologist who specializes in breast

cancer. “I was also struck by the fact that in New Haven,

whenever you see people of color with cancer, it’s worse

in so many ways. They may come in later, or the onset

may come at a much younger age, or they may have other

chronic conditions that make it difficult to treat their

cancer. I’ve had a long interest in decreasing cancer health


Bringing CLINICAL TRIALS

8 Yale Cancer Center | Year in Review 2015

disparities in New Haven.”

For decades these disparities didn’t get much attention

from the medical establishment. That has recently started

to change, spurred partly by the Affordable Care Act. Dr.

Silber is determined to add to the momentum.

One of her tools is a new program called OWN IT

(Oncologists Welcome NewHaven Into Trials). OWN

IT’s purpose is to get more minorities from inner city

New Haven into clinical trials for new cancer treatments

conducted at Smilow Cancer Hospital. Minorities are

under-represented in such trials nationwide. The city of

New Haven, for instance, is about two-thirds black and

Latino, yet those groups account for about 12 percent of the

participants in Yale’s cancer clinical trials. (The trials that

Dr. Silber accrues to are more than 50 percent minority.)

One of OWN IT’s tasks is to remove the barriers

keeping minorities out of trials. The first barrier is

mistrust. “People in town have been afraid of being

someone’s research project,” said Dr. Silber. “They say,

‘Why should I do this? Who is this going to help? I don’t

want to be experimented upon.’” To overcome these

suspicions and build trust, says Dr. Silber, physicians

must become more patient and communicate more

clearly. “Everyone has a right to understand what’s

happening to their bodies, and it’s my obligation to

explain it in a way they understand.”

That’s how Dr. Silber convinces her patients to enter

clinical trials at Smilow. Maria Castellani, a mother of

three, had a bout with stage 3 breast cancer in 2011 and

survived, but in June 2014 the disease returned, in the

aggressive triple negative form. It spread to her lungs,

lymph nodes, and bones. She saw four oncologists, one

of whom gave her six months to live. Three of them never

mentioned clinical trials. The fourth suggested a trial, but

instead of explaining it, merely handed Ms. Castellani a

thick packet of baffling technical information.

Distraught and despairing, she finally connected with

According to Dr. Silber, these low numbers have

consequences. First, minorities are missing out on the most

cutting-edge treatments for their cancers, which affects their

survival rates. Second, the lack of minorities can skew trial

results – Dr. Silber has noticed that new medications given

to her patients often don’t live up to their hype.

“So I would go back and look at the trial,” she said,

“and I realized that my patient never would have been

chosen for the study, because it eliminated anyone with

complicating factors like diabetes or high blood pressure

or obesity, which are common among my cancer patients

from the inner city. If you test all your oncologic drugs

only on the healthy, the wealthy, and the wise, your

test doesn’t equate to real life and doesn’t address the

problems we see in New Haven.”

“I’m so grateful for being in this clinical trial,” Ms. Castellani said. “Dr. Silber

was the only doctor who didn’t give up on me. She took her time and gave me

this option, and she explained everything.”


the clinical trial.” During treatment, Dr. Silber asked her

to speak to two Latina patients with breast cancer who

were afraid of trials. “I was kind of an advocate,” said Ms.

Vega, “and I felt good because I was helping someone else

and telling them it’s OK.”

After Wendy Ormond was diagnosed with breast cancer,

she went into a tailspin. She began drinking and contracted

pancreatitis before she could have surgery, and her blood

pressure also shot up. She was referred to Dr. Silber, who

sent her to a heart doctor to get her blood pressure under

control. She also convinced Ms. Ormond to overcome her

terror of doctors and enter a clinical trial. “I trusted her,”

said Ms. Ormond simply. “I knew she wouldn’t get me into

something that would hurt me. I love that lady.” She began

the trial in February 2015, and her blood tests continue to

improve.

OWN IT will address the barriers of fear and mistrust,

says Dr. Silber, by building a relationship between Yale

and the people in the city surrounding it. That will take

time. She has always devoted time to community outreach,

but now new funding from the National Institutes of

Health and other sources will allow her to hire patient

navigators and a community health educator who can hold

educational sessions at community centers, schools, and

churches, to explain clinical trials and their advantages.

She adds that the city’s primary care physicians and

Yale oncologists also need educating. Too many patients

never hear about trials. Patients who don’t speak English

may be rejected as too time-consuming. Some trials

disqualify swaths of inner city minorities because their

blood pressure, cholesterol, or glucose levels tend to be

higher than those of people in wealthier suburbs.

However, Dr. Silber sees signs of change. The NIH,

the National Cancer Institute, and the American Society

of Clinical Oncology all have started paying attention

to health disparities and funding research. Things are

changing at Yale as well. In May, Dr. Silber was appointed

to the Cancer Center’s Executive Committee as Assistant

Director for Diversity and Health Equity.

“We’ve never been at the table before,” said Dr. Silber,

“but because of the leadership at Smilow, there’s a new

awareness of how this needs to be part of the thinking.

Everything is aligning to make OWN IT a way to really

change clinical trials for inner city New Haven.”

Dr. Silber, who suggested a clinical trial with Orteronel.

Ms. Castellani’s mother, brothers, and uncles warned

that she would be treated like a lab rat, but she trusted Dr.

Silber and joined the trial in July 2015. By the end of the

year, her lymph nodes were clear, her lungs were stable,

and her bone cancer was fading.

“I’m so grateful for being in this clinical trial,” she said,

crying a little. “Dr. Silber was the only doctor who didn’t

give up on me. She took her time and gave me this option,

and she explained everything. I don’t have enough to pay

her for what she’s done for me.”

Similarly, Marta Vega was diagnosed with stage 3

breast cancer. Her oncologist was hurried and distant.

Terrified and in denial, she didn’t want to consider

treatment of any kind. Then she saw Dr. Silber, who

carefully explained a breast cancer trial to her and said,

“If you were my sister, I would recommend this.” Her

warmth and patience persuaded Ms. Vega, who received

experimental chemotherapy from March to August 2014.

Her tumor shrank 75 percent, and surgery took care of

the rest. “If it wasn’t for Dr. Silber,” said Ms. Vega, “I

wouldn’t have survived, because I would not have done


Craig Crews, PhD; Peter G. Schulam, MD, PhD; Mark Lemmon, PhD

The Valley of Death: that’s what the co-directors

of the new Yale Cancer Therapeutic Accelerator Program

(Yale CTAP) call the place where promising lab compounds

perish on the rigorous journey towards becoming a new

cancer drug. In fact, most patents of discoveries expire

before they even reach the valley’s outskirts, according

to Craig Crews, PhD, Lewis B. Cullman Professor of

Molecular, Cellular and Developmental Biology, and

Director of the Yale Center for Molecular Discovery, and his

CTAP co-director Mark Lemmon, PhD, David A. Sackler

Professor of Pharmacology and co-director of the Cancer

Biology Institute.

“Despite all the efforts at translational medicine,” said

Dr. Crews, “the harsh reality is that it takes a lot to develop

a tool compound into a drug candidate. There’s still a gap,

the proverbial Valley of Death. An academic can take his

or her research only so far towards translation, because

there aren’t funding mechanisms for it, there isn’t the

training for it, there isn’t the personnel to do it.”

“Basic scientists in the Cancer Center are doing

amazing work,” added Dr. Lemmon, “but there are


NEW DRUGSof NEW DRUGSothers to ask what it would take to make something

attractive enough to put $5 million or $15 million into a

new startup located here,” said Dr. Crews. “So we really

aren’t doing drug discovery or drug development, but

would generate the companies to do that.”

Another part of the program’s mission is to teach YCC

members how to be more entrepreneurial. Once the

external advisory committee approves a project, CTAP will

work with the initiating faculty member to put together

a business plan and coach him/her on how to pitch the

discovery to venture capitalists.

Because the program is so new, the search for funding

has just begun. Dr. Crews and Dr. Lemmon intend to

tap philanthropic and commercial sources that prefer to

invest in projects that have moved beyond basic science

toward practical application. A strong selling point, said

the co-directors, is that CTAP can draw on new state-of-

the-art research facilities and Institutes on Yale’s West

Campus as well as several departments.

“Investors in these new drugs will be getting a lot of

added value here,” said Dr. Lemmon. “It takes a village

to move from a germ of an idea to the exploitation of

the idea.”

huge barriers to taking their discoveries beyond the lab.

Expense and lack of access to the right experience stall

most potential cancer care discoveries. CTAP would

provide stepping stones across the Valley of Death.”

The idea for CTAP came from Peter G. Schulam, MD,

PhD, Director of Yale Cancer Center and Physician-

in-Chief of Smilow Cancer Hospital at Yale-New

Haven (Interim). The program is modeled on a similar

one started by Dr. Crews called PITCH (Program in

Innovative Therapeutics for Connecticut’s Health), which

is also aimed at developing new drugs. PITCH received a

$10 million, three-year grant from the state of Connecticut

to select and fund projects from Yale and the University

of Connecticut, with the goal of developing promising

discoveries to the point where they can be pitched to

venture capital firms.

CTAP will adopt this concept, but with a focus on

generating new cancer drugs and accelerating their

development in much the same way as biotech startups.

“By coalescing ideas, capital, and talent,” said Dr. Crews,

“one can drive the whole drug discovery process in a much

faster way than the pharmaceutical industry has.” CTAP

will bring together programs across multiple schools

and faculties at Yale to leverage their unique strengths in

this process, allowing Cancer Center members to work

alongside faculty who can complement their research goals

from throughout the University.

It would work like this: let’s say a Cancer Center

member makes an intriguing discovery and wants to

develop it into a drug that could be tested in Phase I trials at

Yale, but doesn’t know how to go about it. CTAP and the

Yale Center for Molecular Discovery would engage a team

of professional drug developers to screen drug candidates

for useful compounds. If any of these appeared promising,

medicinal chemists and others would design, synthesize,

and tweak the compounds to make them more drug-like.

CTAP would then help marshal the efforts of labs in the

Cancer Biology Institute and elsewhere to generate data

packages evaluating the potential of the compounds –

facilitating the pipeline from idea to therapeutic approach.

At that point, the compounds would be evaluated by an

external advisory board, comprised of representatives

from biotech and big pharma, to determine which have

therapeutic potential and should advance to the next level:

pitching to philanthropists, venture capitalists, and others.

“We want to work with the venture capitalists and

developmentACCELERATINGACCELERATING

At the age of 23, Josh Scussell was starting his life,

and like most people in their early twenties, cancer was

the last thing on his mind. He was still on his parent’s

insurance and did not have a primary care doctor.

Therefore, when he noticed a lump on his left leg in

the groin area, he went to a walk-in clinic to have it

examined. Thinking it was an abscess, the lesion was

lanced, but when blood, not puss, came out, and Josh’s

leg immediately became red and inflamed, he was

instructed to go to a local Emergency Department.

From that point on, Josh would encounter a lot of

waiting. He was in the ED from 6PM until 9AM waiting

for a room before he could be seen, and from there he

was tested for everything from cat scratch fever to other

infections and eventually a biopsy was performed. During

the biopsy, fluid developed around Josh’s heart and he

went into congestive heart failure. After spending three


Josh and Heather Scussell


days in the ICU his heart rate and oxygen levels returned to normal. His girlfriend at the

time, Heather, now his wife, was by his side throughout the entire endeavor.

“Heather’s mother, who is a nurse, was the first to bring up the possibility of cancer,”

said Josh. “The doctors assured us this was not the case and that a biopsy would confirm

this. Once I was out of the ICU and recovering, I received the results of the biopsy, which

determined I had Non-Hodgkins T Cell Lymphoma. I was in shock and completely

devastated. I was alone in my room at the time, and when my mother came in and

heard the news she was more in shock than I was. It was a very emotional time

for everyone.”

Josh was started on a chemotherapy regimen know as CHOP, an aggressive form of

chemotherapy. An earlier PET scan had revealed the disease had spread to Josh’s lymph

nodes and a large tumor in his groin area. After 6 cycles of treatment with CHOP, Josh’s

PET scan was completely clear. Josh was relieved and was ready to put it all behind him;

however, he soon learned that without a stem cell transplant, the cancer could return

within three months. At this point, it was suggested that he transfer his care and meet

with one of the top T Cell Lymphoma doctors in the country, Dr. Francine Foss at

Smilow Cancer Hospital.

“Dr. Foss got right down to business and explained the next steps in the process, which

helped me keep the momentum going forward,” explained Josh. “I had already been

through a lot, and wasn’t sure I could face a stem cell transplant.”

Just six months since Josh first noticed the lump, he underwent his first transplant,

an autologous transplant where his own stem cells were collected before treatment and

then returned to replace the stem cells that had been damaged by the chemotherapy. He

spent three weeks in the hospital and experienced difficult side effects, but despite this, he

recovered quickly and was back to his normal life after about three months.

A year later, Josh began having back pain. When the pain did not lessen, Dr. Foss ordered

a PET scan and MRI, which revealed a spot that was soon biopsied. The results indicated the

cancer had returned, this time on his T10 vertebrae. “Had we waited any longer,” said Josh “it

would have spread to my spine and this would be a different story.”

For his second transplant, Josh receive an allogeneic transplant along with a new

chemotherapy regimen that targeted a specific protein in the lymph cells, Brentuximab.

An allogeneic stem cell transplantation involves transferring stem cells from a healthy

donor match after chemotherapy in patients where their cancer has relapsed. Dr. Foss

commented, “Josh’s story is a tremendous success story for the use of newer therapies.

Love Knows no Bounds,Not Even Cancer

When patients relapse after autologous therapies, it’s often difficult to go on with an

allogeneic transplant because using conventional chemotherapy, the cancer often does

not go into remission. Because Josh did so well with the new drug, Brentuximab, he was

the perfect candidate to go ahead with an allogeneic transplant.”

Six months passed before a donor match was found, but unfortunately the donor

decided at the last minute not to go through with stem cell donation for Josh. The search

continued using Be the Match® and Josh received word that a 25-year-old female in

Canada had been located as a near perfect match for him. His transplant was scheduled

two years after his first. Due to insurance issues, the transplant was done in Boston at Dana

Farber. Dr. Foss was kept informed every step of the way. Josh was in the hospital for three

weeks undergoing chemotherapy before the transplant and during this time, Heather spent

every night by his side.

“I couldn’t imagine having to see her go through something like this. She has been with

me from that first night in the ED up until now,” said Josh. “She was commuting from

Boston to Guilford, CT every day for almost a month. She had to wear a full gown and

mask, and never once complained. We have been together for seven years, and over half of

that has been dealing with this cancer. I knew after that, she would always be by my side,

and so I asked her if I could spend the rest of my life by hers. She said yes.”

Following the transplant, due to the high risk of infection, Josh had to undergo one

year of isolation where he couldn’t leave the house. He lost 50 pounds and recovery was

slower this time around. A year post transplant, Josh was eager to contact his donor,

the 25-year-old woman from Canada. As it turns out, they had more in common than

just bone marrow. Their birthdays are a month apart, and both got married last year.

Additionally, from Saskatchewan, her husband, a professional hockey player, is a family

friend of Mandi Schwartz, a former Yale University ice hockey player that passed away

from acute myeloid leukemia in 2011. For five years, Yale University has been helping save

lives through marrow donor registration drives in honor of Mandi, including one that was

held in Mandi’s hometown, Saskatchewan, Canada, where Josh’s donor volunteered and

decided to join the registry.

“Her husband’s best friend had leukemia and did not survive his transplant, so when

they did not hear from me after six months, they thought I had not survived either,” said

Josh. “I was able to receive her contact information after one year, and they were very

happy to hear from me. My first email to her was titled ‘You saved my life’ and from there

we began exchanging photos and information about each other. One of the photos she

sent was of her on donation day with the bag of stem cells. It was flown in that day and I

remember seeing the bag and touching it. And there she was in a gown, holding the bag of

cells and smiling. It was very emotional for me to see that.”

This past October, one year and three months after his second transplant, Josh and

Heather were married and honeymooned in Disney World. “I was really excited to hear

that Josh and Heather got married. He has been a tremendous success story and I am

“I was really excited to hear that Josh and Heather got married. He has been a tremendous success story and

I am so happy for them.” - Dr. Francine Foss

14 Yale Cancer Center | Year in Review 2015 7yalecancercenter.org | Yale Cancer Center

so happy for them. It was so exciting to see the picture of

Josh and his bride at their wedding – I felt like it was my

son getting married,” Dr. Foss said.

“It truly meant a lot to see how genuinely happy Dr.

Foss was for me when I got married,” said Josh. “She

helped me through this difficult time, by more than just

treating me, but by supporting me.”

Josh and Heather are looking forward to a long life

together. They will never forget the woman that saved his

life and plan to meet her and her husband this spring. Her

small gesture in joining the bone marrow registry created a

big connection spanning thousands of miles, and allowed

for Josh and Heather’s happy ending to be possible.

“I knew after that, she would

always be by my side, and so I

asked her if I could spend the rest

of my life by hers. She said yes.”


Yale scientists have pioneered a new form of

positron emission tomography (PET). This new approach

to imaging may allow cancer-care specialists to detect the

epidermal growth factor receptor (EGFR), a target for

cancer therapy that is expressed on the surface of tumor

cells. This new type of PET scan will also monitor drugs

that target the EGFR in tumors and could provide a new

way to image their effectiveness in patients.

The most common form of PET scan is called

fluorodeoxyglucose (FDG)-PET, in which a cancer patient

is given a radioactive sugar that accumulates in the tumor,

allowing doctors to view it. The Yale group is using PET

technology in a way that hasn’t been done before. Their

new technique uses a radiolabeled drug that specifically

binds to the EGFR. The goal is to provide a method for

doctors to see the tumor, watch the uptake of the drug,

and monitor its effectiveness.

“That’s what we’re really excited about,” said Joseph

Contessa, MD, PhD, Associate Professor of Therapeutic

Radiology and Pharmacology whose laboratory studies

the biology of EGFR. “We have not previously been able

to non-invasively monitor the interaction of a cancer

drug with its target in patients. With this work we hope to

translate our knowledge about the biology of EGFR to a

simple and clinically useful PET scan.”

PET imaging of the EGFR is accomplished by using a

radiotracer called [11C]-erlotinib. Erlotinib is a drug that

blocks activation of the EGFR, and potently blocks the

growth of tumor cells with mutation of the EGFR. EGFR

mutations are found in multiple cancers and come in

many forms. Those with tyrosine kinase mutations, which

activate the receptor’s activity, are the Yale team’s current

focus. The radiolabeled form of erlotinib was planned

and synthesized by a member of the team, radiochemist

Yiyun Henry Huang, PhD, Professor of Radiology and

Biomedical Imaging, and Co-Director of The Yale PET

Center. Dr. Huang replaced one of the drug’s carbons with

a radioactive carbon, which allows the compound to be

traced by PET.

The team tested the technique by inject ing

[11C]-erlotinib into mice with lung cancer tumors

harboring EGFR mutations. Evan Morris, PhD, Associate

Professor of Radiology and Biomedical Imaging,

Psychiatry, and Biomedical Engineering, and Co-Director

of the PET Imaging Section, modeled the radiotracer’s

distribution and the team was able to watch the drug bind

to the tumor. This revealed the presence of the mutation

and the effectiveness of the drug in blocking EGFR activity.

Their revelation could be a big step in the treatment

of NSCLC, explained Dr. Contessa, because a physician

Radiobiology and Radiotherapy RESEARCH PROGRAM

can see whether the drug is hitting the target at every site

in the body. If tumors are not imaged by [11C]-erlotinib

PET, doctors can consider using another tyrosine kinase

inhibitor or irradiating the sites missed by the drug. The

technique can also reveal when patients are developing

resistance to a drug, either generally or at certain sites, and

hence could benefit from changing or supplementing their

therapies. “We hope this technique will help physicians

make these decisions earlier, by giving them more

information more quickly,” said Dr. Contessa.

The next step, beginning now, is a Phase I trial with

about two dozen patients at Smilow Cancer Hospital.

That’s where the fourth member of the team comes in,

medical oncologist Sarah Goldberg, MD, MPH, Assistant

Professor of Medicine. “Dr. Goldberg is very interested in

using this new technique to improve therapeutic decision-

making for patients with EGFR mutations,” said Dr. Contessa.

The team believes this technique can be used for other

types of cancer. “There are other tumor sites with specific

mutations, and we might be able to develop radiotracers

that specifically interact with those mutant proteins to

give us a way to image different types of tumors,” said Dr.

Contessa. “We think we can start to personalize imaging

to find mutations, and use imaging as a way to gauge

responses to therapy.”


Evan Morris, PhD and Joseph Contessa, MD, PhD

Imaging the Epidermal Growth Factor Receptor

Texting to Check in on Patients

Sarah Mougalian, MD

Sarah Mougalian, MD , Assistant Professor

of Medicine, specializes in treating patients with

breast cancer. She found herself frustrated by one

aspect of their care. Most breast cancers – about 75

percent – are fueled by the hormone’s estrogen and/

or progesterone. After patients with this type of breast

cancer finish their primary treatments, typically surgery

and perhaps followed by radiation and/or chemotherapy,

they are prescribed a medication to regulate their

hormones, with the goal of preventing a recurrence of

cancer. The regimen sounds simple – one pill every day

for five to ten years.

Yet many of these patients do not follow this regimen.

At Smilow Cancer Hospital, said Dr. Mougalian, it’s

about 25 percent, and some studies have found non-

adherence rates up to 50 percent. The reasons range from

forgetfulness to unfilled prescriptions to intolerance of the

medication’s side effects. Failure to take the medication or

to complete the long-term therapy may put these patients

at higher risk of recurrence. Hence Dr. Mougalian’s

frustration, which has led to an innovative solution.

Many of Dr. Mougalian’s patients are young women,

and she noticed that when she entered an examining

room, they often were texting on their smart phones. “So

we thought about creating a text messaging system to help

people remember to take their medication and to identify

any problems early,” explained Dr. Mougalian. “It can be

three to six months between appointments, a long time

to wait if you have questions. In some cases, people stop

taking their medication and we don’t even know it.”

Dr. Mougalian collaborated with the technology

company CircleLink Health to design a new idea in

cancer treatment – a pilot study built around automated

text messages. She enrolled 100 patients for three months.

All of them received a daily text asking if they had taken

their medication. They type “Y” for yes or “N” for no.

Anyone who didn’t reply or who texted N for three

straight days or six times within 30 days received a phone

call from a triage nurse to find out what was going on.

“This is an effort to identify people who are at risk of

discontinuing their medication, and to try to address it in

real time,” said Dr. Mougalian.

Every patient also got a weekly text asking whether they

were experiencing any of the listed side effects, and if so, to

rate them on a scale of severity from one to nine. Anyone

who reported severe side effects received a phone call to

discuss behavioral modifications or were offered a sooner

appointment with their physician. Patients could also free-

text non-listed side effects.

Finally, patients got one text per month asking if

Cancer Prevention and Control RESEARCH PROGRAM

anything was preventing them from continuing their

medication, such as side effects or finances.

Dr. Mougalian wanted to know whether patients

would be irritated by the daily texts, or if they would

develop “alert fatigue” and delete the reminder without

replying. Only one patient complained. “Lots of patients

say they like it, because they feel like somebody is

looking out for them,” said Dr. Mougalian, “and it’s also

an accountability tool, because they know someone is

checking up on them.”

The text system also seemed to improve adherence:

only five of the 100 patients stopped taking their

medication (four due to side effects), a much higher rate

of adherence than is typical. Dr. Mougalian cautions

that this finding is preliminary. She hopes to test it in a

long-term randomized study and has applied for funding

to do a five-year investigation with 400 patients, half of

them using the text system and the other half not, as a

control group.

“The ultimate goal,” she said, “is to see whether better

adherence correlates to better survival in the long run.”


“The ultimate goal is to see whether

better adherence correlates to better

survival in the long run.”

Not every lab discovery leads directly to

a clinical application, but progress in cancer

care depends on insights from basic science into the

fundamental mechanisms of biology.

A recent paper in the journal Cell offers a good

example. Scientists from Yale Cancer Center and

elsewhere have been studying links between lymphoma

and a biological mechanism called V(D)J recombination.

This mechanism recombines broken pieces of DNA,

and is essential for the development of T cells and B

cells, lymphocytes that form the adaptive immune

system. Yet this process of genetic recombination is

also risky. The paper’s lead author, Grace Teng, PhD, a

postdoctoral fellow and Associate Research Scientist in

Immunobiology, wrote that these developing T and B cells

“perch on the edge of genomic instability.”

“When broken DNA ends are flopping around in the

cell, they can become joined in a haphazard fashion,”

explained Dr. Teng. “A lot of cancers are associated

with these erroneous repair processes. The fact that

lymphocytes have to go through programmed DNA

damage during development makes them particularly

susceptible to errors. That’s why lots of lymphomas stem

from B and T cells.”

In short, the mechanism that creates our adaptive

immune system also exposes us to the risk of lymphoma.

“New lymphocytes are being generated in our bodies at

a tremendous rate every day,” said another of the paper’s

authors, David Schatz, PhD, Professor of Immunobiology

and of Molecular Biophysics and Biochemistry, “and

the V(D)J recombination process happens hundreds

of millions, if not billions of times per day. So the risk is

ongoing and chronic, and even an extremely low error rate

gives you a significant risk.”

Dr. Teng’s research also uncovered an unexpected

wrinkle in V(D)J recombination: breaks of DNA in the

“wrong” places. In V(D)J recombination, DNA is cut by

two proteins called recombination activating genes 1 and 2

(RAG1 and RAG2), which Dr. Schatz discovered 25 years

ago. They were thought to cut DNA in a small, limited part

of the genome, as a way of protecting the rest of the genome

from flawed cuts. But Dr. Teng and her colleagues found

RAG1 and RAG2 in thousands of off-target sites. “That

seemed to constitute a much broader, more significant

threat than previously suspected,” said Dr. Schatz.

Dr. Teng and colleagues knew that the RAG

complex prefers to sever DNA at specific spots called

Recombination Signal Sequences (RSSs), which are

abundant in the normal cutting sites. Researchers found

that in the off-target sites, RSSs are significantly depleted.

Cancer Immunology RESEARCH PROGRAM

That means fewer places for RAG to cut, which lessens the

risk of incorrectly refitted strands of DNA.

“You end up with two different compartments of the

genome,” said Dr. Teng, “one enriched with RSSs, and

another where there’s not much of the DNA sequence for

RAG to cut.” This compartmentalization seems to protect

the genome from inappropriate cuts in the off-target sites.

That begs another question: why didn’t evolution

remove this bug from the system? Dr. Schatz points out

that RAG1 and RAG2, with the threat of lymphoma they

carry, have been present during vertebrate evolution for

hundreds of millions of years. The depletion of RSSs at off-

target sites might be evolution’s way of putting the threat

on the back-burner.

“Cancer is generally a disease of old age,” said Dr.

Schatz, “and hence lymphomas that would kill people at

50 or 60 would have been a very weak evolutionary force

for most of human evolution. I suspect that’s why this

hasn’t been completely selected against.”

These discoveries might someday help physicians

predict which parts of the genome are at greatest risk

of lymphoma. “As basic scientists,” said Dr. Schatz, “we’re

not looking at how the immune system is interacting

with tumors, but at what gave rise to the tumors in the

first place.”


Grace Teng, PhD and David Schatz, PhD

The Immune System and the Risk of Lymphoma

Jorge Galan, PhD, DVM

The Links Between Typhoid, Bacteria, and Cancer

A discovery by a Yale Cancer Center

researcher promises to beget a vaccine against one of

the world’s most deadly diseases, typhoid fever. This

breakthrough is also likely to cause two important side

effects: a decline in the incidence of gallbladder cancer,

and more research on the links between bacterial

pathogens and cancer.

Typhoid fever is one of the scourges of public health,

sickening more than 20 million people every year and

killing 200,000, almost all of them in undeveloped

countries, where it is spread by contaminated food

or water, usually via the feces of infected people. The

infectious cause of typhoid has been known for more than

a century, a bacterium named Salmonella Typhi. But the

bacteria’s mechanism to cause disease has been a mystery,

preventing the development of a knock-out vaccine, one

of the holy grails of public health.

That may soon change. A team led by Jorge Galan,

PhD, DVM, Lucille P. Markey Professor of Microbial

Pathogenesis and Cell Biology, and Chair of Microbial

Pathogenesis, has identified the basis for Salmonella

Typhi’s unique virulence properties. Dr. Galan’s

team identified “typhoid toxin,” which is produced

by Salmonella Typhi and in experimental animals, can

reproduce most of the symptoms of typhoid fever.

Dr. Galan’s team has also solved the atomic structure

of “typhoid toxin,” which should make possible the

development of small molecule inhibitors to block the

infection, as well as a vaccine that could potentially

eradicate typhoid fever.

“This discovery turned the disease upside down,” said

Dr. Galan. “Now we know why S. Typhi causes typhoid

fever, and we can create a vaccine against it. That’s the main

impact.” The Bill & Melinda Gates Foundation has put Dr.

Galan’s breakthrough onto a fast track towards a vaccine.

The discovery also provides a molecular explanation for

the epidemiological link between typhoid and gallbladder

cancer. Many survivors of typhoid become asymptomatic

carriers of S. Typhi, and hold the bacteria in the gallbladder.

“We discovered that S. Typhi encodes what is essentially

a genotoxin – a toxin that damages the genome’s DNA,”

said Dr. Galan. “So the tumorigenesis is likely to be related

to the toxin’s ability to damage the DNA. When the DNA

is mis-repaired, mutations are created, providing the

basis for the development of cancer. So a vaccine against

typhoid fever should also prevent gallbladder cancer.”

That would be significant in the developed world as

well. About 10,000 new cases of gallbladder cancer are

diagnosed in the United States each year, and 4,000 people

die from it.

Virus and Other Infection-associated Cancers RESEARCH PROGRAM

Dr. Galan believes that the connections between cancer

and infections, especially bacterial infections, deserve more

attention. “This story of ours is one more example. Cancer

researchers sometimes forget that 20 percent of known

cancers are caused by an infectious organism,” he said,

“and that’s probably a gross underestimate, because it only

captures instances where the microorganism is the direct

cause – for example, in the case of human papillomavirus

(HPV) and cervical cancer, or the bacterium Helicobacter

pylori and stomach cancer.”

In far more instances, he added, bacteria and viruses

are most likely predisposing factors that essentially tilt the

scale leading to cancer. “There are many cases of bacteria

that produce genotoxic agents, particularly bacteria that

hang around in the gut, and the thought is that some of

these bacteria could be predisposing factors, for example,

for colon cancer. It is also widely believed that the resident

microbiota in our body most likely plays an important role

in predisposing to certain types of cancer. This is a frontier

that we’re just beginning to explore.”

It is also the impetus behind the name change of the

Research Program from Molecular Virology to Virus

and Other Infection-associated Cancers. “The idea is to

broaden the focus, to think about other microorganisms as

cancer causing agents and not just viruses,” said Dr. Galan.


Cells constantly produce new proteins, which

wear themselves out doing cellular labor. Spent proteins

are tagged for removal by a maintenance protein called

ubiquitin, and then sent to the proteasome, the body’s

equivalent of the glue factory. There, the old proteins

are broken down and discarded. This process is called

protein degradation.

Craig M. Crews, PhD, Lewis B. Cullman Professor of

Molecular, Cellular and Developmental Biology, has been

studying this process for years, looking for ways to control

it with drug-like molecules that target cancer-causing

proteins. His lab’s first foray into this field led to the drug

Kyprolis® (carfilzomib), approved in 2012 for use against

multiple myeloma. Kyprolis® is a proteasome inhibitor

that prevents the degradation of protein in cancer cells,

causing a toxic build-up that kills them.

Now Dr. Crews and his colleagues have developed

a different line of attack. “Instead of blocking protein

degradation,” said Dr. Crews, “we’re inducing it. We’ve

developed a drug strategy whereby the drug enters the cell,

seeks out and binds to rogue cancer-causing proteins, and

drags them to the proteasome for degradation. It’s a seek

and destroy approach.” These drug-like molecules, called

PROTACs (Proteolysis-Targeting Chimeras), were first

reported by Dr. Crews in 2001.

Most targeted cancer drugs are inhibitors that bind

to receptors and block the mutant proteins that cause

cancer. “But when the drug leaves the system, the protein

can start working again,” Dr. Crews explained. “So, to get

the clinical benefit, you need to maintain a high level of

the drug in the body. What we’re doing is different. It’s

not binding and gumming up the process, it’s tricking

the cell’s own quality control machinery to destroy rogue

proteins. It’s also permanent. And the drug survives to

eat its way through a protein population, so in theory,

one needs less of our drug. This approach should greatly

reduce the side effects that accompany high dosing in the

inhibitor paradigm.”

Another strength is the strategy’s broad reach. Dr.

Crews points out that each cell contains an estimated

20,000 different proteins, but only about 25 percent

are potentially vulnerable to inhibitors, which work by

binding receptors or blocking enzymatic functions. That

leaves the great majority of proteins untouched, such as

scaffolding proteins and transcription factors. Since Dr.

Crews’ approach doesn’t depend on inhibition, it should

work against this so-called ‘undruggable’ majority.

The science of tagging and eliminating oncogenic

proteins is new, and so is the technology that makes

it possible: a new class of small-molecule PROTACs

Developmental Therapeutics RESEARCH PROGRAM

designed by Dr. Crews and his lab, a collection of

cell biologists, biochemists, medical chemists, and

pharmacologists. Dr. Crews believes that small-molecule

PROTACs open up wide new possibilities for cancer

therapies. He has started a company called Arvinas to

explore them and to develop the technology further.

For now, Dr. Crews and his partners are interested in

developing PROTACs for leukemias, lymphomas, prostate

cancer, breast cancer, and lung cancer. “But this approach

doesn’t really have any limitations with respect to cancer

type,” said Dr. Crews. “It’s a platform technology, so the

learning around developing one drug could be applied to

address the oncogenic proteins that cause different cancers

in different tissues.” He hopes that clinical trials for

prostate cancer will begin sometime next year.

The National Institutes of Health (NIH) noticed this

breakthrough and Dr. Crews was recently selected for the

inaugural class of a new program at the NIH. He received

an Outstanding Investigator Award and funding of $1

million for each of the next seven years.

“I’m very fortunate that for the last 20 years my lab has

worked right at the interface of chemistry and biology.

It allows me to recognize the important questions in

biology and allows my lab to then go out and tackle those

problems using chemical approaches,” said Dr. Crews.


Molecules That Seek and Destroy Mutant Proteins

Craig M. Crews, PhD

Michael Krauthammer, MD, PhD

Bioinformatics Boosts Cancer Research


Biomedical informatics is changing our

understanding and treatment of cancer. That was recently

illustrated when a team of Yale Cancer Center scientists

used molecular sequencing and computational biology to

reveal startling new information about melanoma.

The team analyzed exome data from 213 melanoma

patients, the second largest such screening ever done.

“We were looking for a better understanding of all the

types of mutations that must happen for melanoma to

occur,” said Michael Krauthammer, MD, PhD, Associate

Professor of Pathology.

They found several surprises. Scientists already knew

that most melanomas stem from mutations in either the

BRAF gene (about 50 percent) or the NRAS gene (20 to

30 percent), but the mutations that caused the remaining

20 to 30 percent were unclear. Researchers did know that

some melanomas contained mutations in the NF1 gene,

but NF1’s role wasn’t well defined.

The Yale screen, conducted as part of the Yale SPORE

in Skin Cancer, showed that mutations of NF1 account

for 10 to 15 percent of melanomas, making them the

third most important driver of the cancer. Further, NF1

mutations help activate the MAPK pathway, the same one

activated by oncogenic mutations in BRAF and NRAS.

“This moves patients with an NF1 mutant melanoma

into a much better understood category,” explained

Dr. Krauthammer, “particularly because it’s acting on

a pathway for which we already have multiple drugs

available. We didn’t have this knowledge before.”

There were other surprises. First, the genome of NF1

patients was much more mutated than those of other

melanoma patients. Second, patients in the NF1 subgroup

were also much older.

“That puzzled us,” said Dr. Krauthammer. “Why

would they have so many more mutations – thousands

of them – and be older?” The researchers noticed that

NF1 mutations didn’t seem to be strong activators of

MAPK. “That led to the interesting hypothesis that maybe

these NF1 melanomas have to reside in the body longer

and acquire more mutations to become as active and

malignant as a BRAF or NRAF melanoma.”

The research team discovered that NF1 melanomas were

acquiring additional mutations from a parallel disease,

RASopathies. RASopathies are developmental disorders,

such as Noonan syndrome and Neurofibromatosis, caused

by germline (inherited) genetic mutations, as distinct

from somatic mutations in cancer, which happen after

conception and can’t be inherited. RASopathies were not

known to be related to melanoma, but they do activate

the MAPK pathway – the same one used by NF1. Dr.

Cancer Genomics, Genetics, and Epigenetics RESEARCH PROGRAM

Krauthammer and his team found that the mutations

in RASopathies were identical to those in mutated

NF1. Further analysis suggested that NF1 mutations by

themselves are too weak to cause melanoma, but when

joined with RASopathy mutations, the combination may

activate the MAPK pathway for melanoma.

These findings began with the analysis of 20,000 genes

for the mutations most important to melanoma. They

have narrowed the list to about 100 genes – still a sizable

number. “Melanoma has so many more mutations than

other cancers,” said Dr. Krauthammer, “but we were

able to identify a key subset of genes that we are going

to sequence across a large cohort of melanoma patients

that are treated at Yale. That will give us a big hint

about what his or her response will be to the targeted

therapies already in use against melanoma, or possibly to

the new immunotherapies.”

The fact that so many mutated genes are implicated

in melanoma is altering our understanding of cancer.

“Suddenly it’s less about whether a disease is a

developmental delay, or a skin cancer, or a blood cancer,”

he added, “and more about the underlying molecular

mechanism. That’s why bioinformatics is so useful in

modern cancer research – to analyze a lot of data, recognize

patterns, and establish links to mutations in other diseases.”

“There is a bit of a misplaced emphasis in

the clinic and in clinical science as to how we think

about targeting cancer,” said Andre Levchenko, PhD,

John C. Malone Professor of Biomedical Engineering and

Director of the Yale Systems Biology Institute. “There

has been a strong focus on controlling primary tumor

growth, even though we know that more than 90 percent

of cancer deaths occur because of invasive cell behavior,

or metastasis. The main problem isn’t the growth of

the primary tumor, it’s the ability of cancer cells to

change their behavior to invasive migration and travel to

secondary sites.”

The emphasis on tumor growth, he added, stems partly

from the difficulty of studying the causes and engines of

cancer cell migration. That’s changing, thanks to new tools

and technologies, some of them unique to Dr. Levchenko’s

lab, where custom-built devices and new methods of

analysis are allowing researchers to trace the movement

of cancer cells, the cues that incite their invasion, and the

signals that guide them to new locations during metastasis.

“Their circuits get rewired,” said Dr. Levchenko,

“so instead of staying put, they start moving toward

this big highway system, the bloodstream.” Eventually

they navigate toward tissues very different from their

native environments, constantly adjusting to different

circumstances, and colonize. “The process is very complex

and not well understood,” said Dr. Levchenko, “but it’s a

systems problem, so we need to use systems approaches.”

His lab and other groups at the Systems Biology

Institute, which he has been leading for the past two

years on Yale’s West Campus, are trying to understand

what transforms site-specific tumor cells into a far-

ranging invasive army. What networks of molecules

mediate this switch? How do invasive cells communicate

and coordinate? Which neighboring cells resist? Which

collaborate with the invaders? How do cancer cells

develop new behaviors and change the behaviors of

neighboring cells?

Many of the answers lie within the complex system

of signaling networks, the fundamental interest of Dr.

Levchenko’s lab and the Institute. In cancer, normal

communication between cells gets misinterpreted,

disrupted, or corrupted. “If we can understand the

signaling mechanisms,” he said, “we can develop new

therapies that prevent invasive spread – for instance, by

rewiring these networks. There’s already a lot of activity to

generate novel therapeutics to do that, and we are working

with others to determine the fastest translational path for

clinical applications. That’s the ultimate goal.”

They are concentrating on what Dr. Levchenko calls

Signal Transduction RESEARCH PROGRAM

“the champions of invasive behavior” – glioblastoma

and melanoma, two of the most deadly and fast-moving

cancers, and also breast cancer, another aggressive

malignancy. A recent paper described how individual

metastasizing breast cancer cells become generally

exploratory, searching for the bloodstream, and then,

in response to a cue, suddenly band together in one

direction, as if they have received their orders of invasion.

“As soon as there is a clear indication of where they want

to go,” explained Dr. Levchenko, “they begin moving

almost in goose step with each other.”

He and his colleagues were able to collect this

extraordinary information by building devices that can

track the path of a single cell and its changing behaviors in

response to cues and signaling networks. These tools give

the scientists novel ways to investigate and analyze a single

cell, looking at every gene, at the metabolizing proteins,

and other factors.

He believes that understanding the complexity of

signaling networks and the process of metastasis demands

a multidisciplinary approach. The teams he has put

together at his lab and institute include researchers of

diverse disciplines: evolutionary biologists, synthetic

biologists, and systems biologists, but also physicists,

mathematical modelers, and biomedical engineers.


Decoding the Signals of Metastasis

Andre Levchenko, PhD

Yale Cancer Center

Peter G. Schulam, MD, PhDInterim Director

Daniel C. DiMaio, MD, PhDDeputy Director

Kevin Vest, MBA, FACHEDeputy Director, Finance and Administration

Mark A. Lemmon, PhDCo-Director, Cancer Biology Institute

Robert Garofalo, PhDAssociate Director, Research Affairs

Roy S. Herbst, MD, PhDAssociate Director, Translational Science

Howard S. Hochster, MDAssociate Director, Clinical Sciences

Melinda L. Irwin, PhD, MPHAssociate Director, Population Sciences

Patricia M. LoRusso, DOAssociate Director, Innovative Medicine

David F. Stern, PhDAssociate Director, Shared Resources

Joann B. Sweasy, PhDAssociate Director, Basic Science

Anees B. Chagpar, MDAssistant Director, Global Oncology

Beth Jones, PhD, MPHAssistant Director, Diversity and Health Equity

Harriet Kluger, MDAssistant Director, Education and Training

Yale Cancer Center Research Programs

Cancer Genomics, Genetics, and EpigeneticsMarcus W. Bosenberg, MD, PhDLajos Pusztai, MD, DPhil

Cancer ImmunologyLieping Chen, MD, PhDMadhav V. Dhodapkar, MD, PhD, MBBS

Cancer Prevention and ControlMelinda L. Irwin, PhDXiaomei Ma, PhD

Developmental TherapeuticsKaren S. Anderson, PhDBarbara A. Burtness, MD

Virus and Other Infection-associated CancersWalther H. Mothes, PhDWendell G. Yarbrough, MD

Yale Cancer Center Shared Resources

Biostatistics and BioinformaticsPeter Peduzzi, PhD

Cesium IrradiatorRavinder Nath, PhD

Clinical Research ServicesHoward S. Hochster, MD

Flow CytometryAnn Haberman, PhD

Pathology Tissue ServicesDavid Rimm, MD, PhD

Rapid Case AscertainmentRajni Mehta, MPH

Yale Center for Genome AnalysisShrikant Mane, PhD

Yale Center for Molecular DiscoveryCraig Crews, PhD


Yale Cancer Center Leadership

Radiobiology and RadiotherapyPeter M. Glazer, MD, PhDJoann B. Sweasy, PhD

Signal TransductionDaniel P. Petrylak, MDDavid F. Stern, PhD

Gary Kupfer, MDAssistant Director, Pediatrics

Ruth McCorkle, RN, PhDAssistant Director, Psychosocial Oncology

Peter G. Schulam, MD, PhDAssistant Director, Surgery

Andrea Silber, MDAssistant Clinical Director, Diversity and Health Equity

Jeffrey Sklar, MD, PhDAssistant Director, Pathology & Tissue Acquisition Services

Edward Snyder, MDAssistant Director, Membership


Smilow Cancer Hospital at Yale-New Haven

Peter G. Schulam, MD, PhDPhysician-in-Chief (Interim)

Abe LopmanSenior Vice President, Operations and Executive Director

Rogerio C. Lilenbaum, MDChief Medical Officer

Catherine Lyons, RN, MSExecutive Director, Smilow Patient Care Services

Kerin B. Adelson, MDChief Quality OfficerDeputy Chief Medical Officer

Anne Chiang, MD, PhDChief Network OfficerDeputy Chief Medical Officer

Benjamin L. Judson, MDMedical Director, Ambulatory ClinicsDeputy Chief Medical Officer

Michael D. Loftus Vice President, Financial Operations

Arthur LemayExecutive Director, Smilow Cancer Network

Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven have joined forces to create Closer to Free, a fund that provides essential financial support for break-through cancer research and compassionate patient care. Learn More >> www.giveclosertofree.org

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Smilow Cancer Hospital Clinical Programs

Brain Tumor Clinical Program Leader:Joachim M. Baehring, MDDisease Aligned Research Team Leader:Kevin P. Becker, MD, PhD

Breast Cancer Clinical Program Leader:Anees B. Chagpar, MDDisease Aligned Research Team Leader:Lajos Pusztai, MD, DPhil

Endocrine CancersClinical Program and Disease Aligned Research Team Leader:Tobias Carling, MD, PhD

Gastrointestinal CancersClinical Program and Disease Aligned Research Team Leader:Howard S. Hochster, MD

Gynecologic Cancers Clinical Program Leader:Peter Schwartz, MDDisease Aligned Research Team Leader:Alessandro D. Santin, MD

Head and Neck Cancers Clinical Program Leader: Wendell G. Yarbrough, MDDisease Aligned Research Team Leader:Barbara A. Burtness, MD

Hematology Clinical Program Leader: Steven D. Gore, MDDisease Aligned Research Team Leader:Madhav V. Dhodapkar, MD, PhD, MBBS

Melanoma Clinical Program Leader:Stephan Ariyan, MDDisease Aligned Research Team Leader:Mario Sznol, MD

Phase IClinical Program Leader:Patricia M. LoRusso, DO Disease Aligned Research Team Leader:Joseph Paul Eder, MD

Prostate and Urologic Cancers Clinical Program Leader: Peter G. Schulam, MD, PhDDisease Aligned Research Team Leader:Daniel P. Petrylak, MD

SarcomaClinical Program Leader:Gary E. Friedlaender, MDDisease Aligned Research Team Leader:Dieter M. Lindskog, MD

Therapeutic Radiology Clinical Program Leader:Lynn D. Wilson, MD, MPHDisease Aligned Research Team Leader:Roy H. Decker, MD, PhD

Thoracic Oncology Clinical Program Leader:Frank C. Detterbeck, MDDisease Aligned Research Team Leader:Roy S. Herbst, MD, PhD

Pediatric Hematology and OncologyClinical Program and Disease Aligned Research Team Leader:Gary Kupfer, MD

Allen Everett BaleLinda M. BartoshukSusan J. BasergaLauren Paige BlairJean L. BologniaMarcus W. BosenbergDemetrios BraddockTobias CarlingNancy CarrascoSidi ChenKeith Adam ChoateLynn CooleyJose CostaBernard G. ForgetAlan GarenMark B. GersteinAntonio J. GiraldezMurat GunelShangqin GuoRuth HalabanStephanie HaleneShilpa HattangadiChristos HatzisErin Wysong HofstatterJosephine J. HohNatalia B. IvanovaSamuel G. KatzSajid A. KhanKenneth Kay KiddYuval KlugerWilliam H. KonigsbergDiane S. Krause

Rossitza LazovaDavid J. LeffellPeter LengyelPeining LiRichard P. LiftonHaifan LinXavier LlorJun LuShrikant M. ManeMiguel A. MaterinJames Michael McGrathKarla NeugebauerJames P. NoonanManoj PillaiManju PrasadLajos PusztaiPeter E. SchwartzEmre U. SeliGerald S. ShadelJeffrey L. SklarMatthew Perry StroutHugh S. TaylorJeffrey TownsendRobert UdelsmanScott Donald WeatherbeeSherman Morton WeissmanAndrew Zhuo XiaoMina LuQing XuTian XuQin YanHongyu Zhao

Stephan AriyanPhilip William AskenaseKevin Patrick BeckerJeffrey R. BenderAlfred L. M. BothwellRichard BucalaLieping ChenOscar Rene ColegioJoseph Edgar CraftPeter CresswellKavita DhodapkarMadhav V. DhodapkarRichard L. EdelsonBrinda EmuRichard A. FlavellFrancine M. FossMichael GirardiEarl John GlusacAnn M. HabermanDavid HaflerDouglas John HanlonPaula B. KavathasSteven H. KleinsteinSmita KrishnaswamyMark Joseph MamulaJennifer Madison McNiffRuslan M. MedzhitovEric R. F. MeffreDeepak NarayanJoao P. PereiraJordan Stuart PoberCarla Vanina RothlinNancy Hartman RuddleKurt SchalperDavid G. SchatzStuart Evan SeropianBrian Richard SmithEdward Leonard SnyderMario SznolRobert E. TigelaarJun Wang

Kerin Bess AdelsonSteven L. BernsteinElizabeth H. BradleyBrenda CartmelAnees B. ChagparElizabeth Brooks ClausAmy Joan DavidoffNicole Cardello DezielRobert DubrowLeah McArthur FerrucciLisa FucitoBonnie Elyssa Gould RothbergCary P. GrossCaitlin Elizabeth HansenTheodore R. HolfordScott Frederick Huntington Melinda Liggett IrwinBeth A. JonesManisha Juthani-Mehta Nina S. Kadan-LottickJennifer M. KapoBrigid KilleleaAnthony W. KimTish KnobfSuchitra Krishnan-SarinStephanie Lynn KweiDonald R. LanninJames Mark Lazenby

Steven B. LederHaiqun LinLingeng LuShuangge Steven MaXiaomei MaAsher Michael MarksRuth McCorkleSherry McKeeRajni Lynn MehtaSarah Schellhorn MougalianLinda M. NiccolaiMarcella Nunez-SmithStephanie Samples O’MalleyJonathan Thomas PuchalskiElena RatnerHarvey A. RischPeter SaloveyTara SanftDena J. Schulman-GreenDave SellsFatma M. SheblSangini S. ShethAndrea Lynn Maria SilberMehmet SofuogluShiyi WangYawei ZhangYong Zhu


Yale Cancer Center Membership

Cancer Epigenetics, Genetics, and Genomics

Cancer Immunology Cancer Prevention and Control


Janet L. BrandsmaDaniel C. DiMaioAyman Sayed El-GuindyJorge E. GalanAndrew GoodmanStanley David HudnallNatalia IssaevaAkiko IwasakiBenjamin L. JudsonSusan M. KaechMichael J KozalMartin Alexander KriegelPriti KumarBrett D. LindenbachRobert E. MeansI. George MillerKathryn Miller-JensenWalther H. MothesElijah Paintsil Noah Wolcott PalmAnna Marie PyleMichael RobekJohn K. RoseAlessandro D. SantinChristian SchliekerJoan A. SteitzRichard E. SuttonPeter John TattersallAnthony N. Van den PolYong XiongWendell Gray Yarbrough

Ranjit S. BindraDaniel J. BoffaDouglas E. BrashDavid Joel CarlsonRichard E. CarsonSandy ChangZhe (Jay) ChenVeronica Lok Sea ChiangJohn W. ColbergJoseph N. ContessaShari DamastRoy H. DeckerJun DengFrancesco DErricoFrank C. DetterbeckJames S. DuncanSuzanne B. EvansPeter Michael GlazerFanqing GuoJames E. HansenHoby Patrick HetheringtonSusan A HigginsZain A. HusainFahmeed HyderRyan B. JensenMegan C. KingGary KupferWu LiuK. Brooks LowMeena Savur MoranEvan Daniel MorrisRavinder NathAbhijit A. PatelRichard E. PeschelKenneth B. RobertsFaye A. RogersPeter SchulamYung H. SonPatrick SungJoann Balazs SweasyLynn D. WilsonSandra L. WolinJames Byunghoon YuZhong Yun

Anton M. BennettKenneth F. BlountTitus BoggonDavid A. CalderwoodLloyd Garnet CantleyToby C. ChaiPietro De CamilliGary Vincent DesirMichael P. DiGiovannaRong FanKathryn M. FergusonJohn P. GeibelSourav GhoshValentina GrecoJaime GrutzendlerMark W. HochstrasserValerie HorsleyMichael E. HurwitzKarl L. InsognaRichard Glenn KibbeyJoseph W. KimAnthony J. KoleskeMichael Oliver KrauthammerTuKiet T. LamMark A. LemmonAndre LevchenkoJoseph Anthony MadriWang MinJon Stanley MorrowPeggy Myung Michael H. NathansonDon X. NguyenDaniel PetrylakKaterina PolitiDavid L. RimmJoseph SchlessingerMartin A. SchwartzDavid F. SternYajaira SuarezDerek K. ToomreBenjamin E. TurkNarendra WajapeyeeRobert Martin WeissKenneth R. WilliamsDan WuJohn Joseph WysolmerskiXiaoyong Yang

Maysa Mahmoud Abu-KhalafKaren S. AndersonMasoud AzodiJoachim M. BaehringAarti Khushal BhatiaDebra Schwab BrandtRonald R. BreakerBarbara Ann BurtnessCharles H. ChaHerta H. ChaoYung-Chi ChengAnne ChiangJennifer Nam ChoiGina G. ChungJason Michael CrawfordCraig M. CrewsHenk De FeyterHari Anant DeshpandeVincent T. DeVitaJoseph Paul EderBarbara E. EhrlichJonathan A. EllmanDonald Max EngelmanTarek FahmyLeonard Raymond FarberJames J. FarrellJean-Francois GeschwindScott Nicholas GettingerSarah B. GoldbergSteven D. GoreYa HaDale HanRoy S. HerbstSeth B. HerzonHoward S. HochsterMichael Edwin HodsdonNina Ruth HorowitzWilliam L. Jorgensen

Developmental Therapeutics Virus and Other Infection-associated Cancers

Radiology and Radiotherapy Signal Transduction

Juliane M. JuergensmeierPatrick A. KenneyHarriet M. KlugerJaseok KooJill LacyJia LiRogerio C. LilenbaumDieter M. LindskogElias LolisPatricia LoRussoScott J. MillerJennifer MoliternoGil G. MorNatalia NeparidzeTerri Lynn ParkerPasquale PatrizioPeter Natale PeduzziAndrew J. PhillipsJoseph Massa PiepmeierNikolai Alexandrovich PodoltsevThomas PrebetLynne J. ReganJohn David RobertsMichal Gillian RoseThomas J. RutherfordW. Mark SaltzmanAlan Clayton SartorelliClarence Takashi SasakiAlanna SchepartzWilliam C. SessaBrian Matthew ShuchDavid Adam SpiegelPreston SprenkleStacey M. SteinSeyedtaghi (Shervin) TakyarVasilis VasiliouDaniel ZeltermanJiangbing Zhou

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